Methods for enriching for duplex reads in sequencing and error correction

A method for preparing a sequencing library from a test sample comprising a plurality of double-stranded DNA molecules, the method comprising:

• (a) obtaining a test sample comprising a plurality of double-stranded DNA (dsDNA) molecules, wherein the dsDNA molecules comprise a forward strand sequence and a reverse complement strand sequence;
• (b) ligating dsDNA adapters to both ends of the dsDNA molecules, generating a plurality of dsDNA adapter-molecule constructs, wherein the dsDNA adapter comprises a unique molecular identifier (UMI);
• (c) incorporating one or more biotin-labeled nucleotides into partially ligated or nicked dsDNA adapter-molecule constructs to create a plurality of labeled dsDNA adapter-molecule constructs;
• (d) depleting the labeled dsDNA adapter-molecule constructs from the test sample;
• (e) amplifying the remaining dsDNA adapter-molecule constructs in the depleted test sample to generate a sequencing library;
• (f) sequencing at least a portion of the sequencing library to obtain a plurality of sequence reads;
• (g) grouping the sequence reads into families based on the UMIs, wherein each family comprises a first set of forward strand sequences each having a first UMI and a second set of reverse complement strand sequences each having a second UMI;
• and
• (h) comparing the sequence reads within each family to generate a consensus sequence for each family, thereby correcting sequencing-derived errors in sequence reads.